Huntington's Disease (HD) is a progressive neuropsychiatric disorder thought to be produced by premature cell death in the striatum and cortex. The symptoms, which are characterized by progressive involuntary movements and dementia, do not generally occur until the third or fourth decade of life. Although genetic markers linked to HD have been localized to human chromosome 4p, the gene has not been cloned. One problem that has prevented the cloning of this gene is the inability to define the gene's exact location. Genetic analysis, including linkage disequilibrium studies have only localized this gene to a chromosomal segment that contains several million basepairs. To avoid cloning and analyzing each gene from this segment, an expression-based system has been developed to find this gene. A key feature of this system is the tissue specificity of this disease. It is likely that the HD gene demonstrates brain-specific expression or brain specific mRNA processing. By examining the expression of each gene from the disease gene region, only a small group will be identified that fulfill these criteria. Using this system, two genes that physically map to the linkage disequilibrium region have been identified. In particular, one of these genes displays a number of physical and biochemical properties that could be related to the HD phenotype. A system is described to examine these two genes for mutations. If no mutation is found in either of these sequences, then a plan is proposed to examine the linkage disequilibrium region for other candidate genes. If a mutation is found in either of these sequences, then several experiments have been designed to initiate the characterization of the disease gene's biochemical function. In either case, extending these studies to the entire HD gene region should allow the identification of this elusive gene.